Clinical Trials /

Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

NCT03012230

Description:

This phase I trial studies the side effects and best dose of ruxolitinib phosphate when given together with pembrolizumab in treating patients with stage IV triple negative breast cancer that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ruxolitinib phosphate together may work better in treating patients with stage IV triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer
  • Official Title: A Phase 1 Study of PD-1 Inhibition With Pembrolizumab Combined With JAK2 Inhibition in Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: MC1534
  • SECONDARY ID: NCI-2016-02057
  • SECONDARY ID: MC1534
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03012230

Conditions

  • Breast Carcinoma Metastatic in the Bone
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, ruxolitinib phosphate)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiTreatment (pembrolizumab, ruxolitinib phosphate)

Purpose

This phase I trial studies the side effects and best dose of ruxolitinib phosphate when given together with pembrolizumab in treating patients with stage IV triple negative breast cancer that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ruxolitinib phosphate together may work better in treating patients with stage IV triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) (JAK2
      inhibition) in combination with fixed dosing of pembrolizumab (anti PD-1) in patients with
      advanced/metastatic triple negative breast cancer (TNBC).

      SECONDARY OBJECTIVES:

      I. To determine the safety profile of pembrolizumab in combination with ruxolitinib.

      II. To estimate clinical tumor response in women with TNBC treated with pembrolizumab in
      combination with ruxolitinib as measured by Response Evaluation Criteria in Solid Tumors
      (RECIST) version (v)1.1.

      TERTIARY OBJECTIVES:

      I. To assess tumor response with immune related (ir)RECIST and associations with PDJ
      amplification, PD-L1, PD-L2, JAK2 and pSTAT3 expression.

      II. To determine the effect of combination targeted blockade on T- and B- cell immunity to
      breast cancer tumor antigens.

      OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and ruxolitinib
      phosphate orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study, patients are followed up every 3 or 6 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, ruxolitinib phosphate)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Ruxolitinib Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  Metastatic (stage IV) triple negative breast cancer that has progressed after at least
             one prior chemotherapy regimen in the metastatic setting; non-measurable disease (i.e.
             bone metastases) is permitted

          -  Histological confirmation of triple negative breast cancer defined as:

               -  Estrogen receptor =< 1% tumor staining by immunohistochemistry (IHC)

               -  Progesterone receptor =< 1% tumor staining by IHC

               -  Her2/neu by fluorescence in situ hybridization (FISH) (ratio =< 1.8) or IHC (0 or
                  1+)

          -  Absolute neutrophil count (ANC) >= 1500/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Total bilirubin =< 1.5 x upper limit normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN or < 5 x ULN if organ involvement

          -  Alkaline phosphatase < 5 x ULN

          -  Serum creatinine =< 2 x ULN or 24 hour creatinine (Cr) clearance > 60 ml/min

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Ability to provide informed written consent and be able to adhere to the study visit
             schedule and other protocol requirements

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Willing to provide blood samples for correlative research purposes

          -  Has existing archived tissue and is willing to consent to providing sample for
             correlative research purposes

          -  Female subjects of childbearing potential should have a negative serum pregnancy =< 7
             days prior to registration

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication; subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year; Note: abstinence is acceptable if this is the
             usual lifestyle and preferred contraception for the subject

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception starting with the first dose of study therapy through 120 days after the
             last dose of study therapy; Note: abstinence is acceptable if this is the usual
             lifestyle and preferred contraception for the subject

        Exclusion Criteria:

          -  Uncontrolled intercurrent illness including, but not limited to, active uncontrolled
             infection, known positive for active infectious hepatitis, type A, B or C (past
             infection allowed), or psychiatric illness/social situations that would limit
             compliance with study requirements; Note: ongoing infection controlled on
             antibiotics/antifungal/antiviral medications are allowed

          -  Any of the following prior therapies:

               -  Cytotoxic chemotherapy =< 14 days prior to registration

               -  Immunotherapy =< 14 days prior to registration

               -  Biologic therapy (i.e. antibody therapies) =< 28 days prior to registration

               -  Radiation therapy =< 14 days prior to registration

               -  Targeted therapies (i.e. PARP inhibitors, =< 7 days or 5 half-lives whichever is
                  shorter)

               -  Receiving any other investigational agent which would be considered as a
                  treatment for the primary neoplasm =< 14 days prior to registration

          -  Active uncontrolled central nervous system (CNS) metastases

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive

          -  Hypersensitivity to ruxolitinib or any of its excipients

          -  Major surgery =< 28 days prior to registration; Note: if subject received major
             surgery, they must have recovered adequately from the toxicity and/or complications
             from the intervention prior to starting therapy

          -  Clinically significant heart disease, including the following:

               -  Active severe angina pectoris prior to registration

               -  Acute myocardial infarction prior to registration

               -  New York Heart Association classification IV cardiovascular disease or
                  symptomatic class III disease

               -  Note: patients with any of the above may be allowed after discussion amongst the
                  investigators including the principal investigator

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to registration

          -  Hypersensitivity to pembrolizumab or any of its excipients

          -  Has had a prior anti-cancer monoclonal antibody (mAb) =< 4 weeks prior to registration
             or who has not recovered (i.e., =< grade 1 or at baseline level) from adverse events
             due to agents administered more than 4 weeks earlier

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy who
             has not recovered (i.e., =< grade 1 or at baseline level) from adverse events due to a
             previously administered agent

               -  Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Any of the following:

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

               -  Is pregnant or breastfeeding, or expecting to conceive or father children within
                  the projected duration of the trial, starting with the pre-screening or screening
                  visit through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has received a live vaccine within 30 days of planned start of registration; Note:
             seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
             attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events assessed by NCI CTCAE version 4.0
Time Frame:Up to 28 days after last dose of study drug
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by cohort and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence.

Secondary Outcome Measures

Measure:Best response defined as best objective status recorded from the start of the treatment until disease progression/recurrence assessed by modified RECIST criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by dose level).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

December 8, 2017